CN104177305A - Novel method for synthesizing thiotriazinone (TTZ) by using mixed solvent - Google Patents
Novel method for synthesizing thiotriazinone (TTZ) by using mixed solvent Download PDFInfo
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- CN104177305A CN104177305A CN201410386187.3A CN201410386187A CN104177305A CN 104177305 A CN104177305 A CN 104177305A CN 201410386187 A CN201410386187 A CN 201410386187A CN 104177305 A CN104177305 A CN 104177305A
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- mixed solvent
- triazine ring
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- methylthiosemicarbazone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
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Abstract
The invention relates to a novel method for synthesizing thiotriazinone (TTZ) by using a mixed solvent. The synthetic process comprises the following steps: performing cyclization reaction on 2-methylthiosemicarbazide, the mixed solvent, diethyl oxalate and sodium methylate at 0-45 DEG C to generate triazine ring sodium salt, and acidifying through hydrochloric acid to obtain thiotriazinone. Due to the use of the mixed solvent, the system viscosity of the synthetic process is greatly improved, the TTZ cyclization yield is increased to be more than 90% (by 2-methylthiosemicarbazide), and the content of a byproduct-1-methyl-5-sulfydryl-1,2,4-triazole-3-methyl carboxylate is less than 0.002%, namely less than 20ppm.
Description
Technical field
The invention belongs to chemosynthesis technical field, relate to the synthetic of a kind of medicine intermediate, be specifically related to a kind of novel method that uses the synthetic triazine ring of mixed solvent.
Background technology
Triazine ring (TTZ) is the key intermediate of synthetic ceftriaxone sodium, after the synthetic 7-ACT of 7-ACA, can synthesize ceftriaxone sodium with DAMA again, be therefore the important intermediate of producing ceftriaxone sodium, plays a part crucial to the production of ceftriaxone sodium.Ceftriaxone sodium, have another name called rocephin, it is the third generation cephalosporin analog antibiotic with milestone significance (commodity are called Ceftriaxone) of being developed by Roche Holding Ag of Switzerland, in nineteen eighty-two in Switzerland's Initial Public Offering, it is first semi-synthetic broad-spectrum long-acting cynnematin, be mainly used in the infection illness due to sensitive organism, as respiratory system infection (especially pneumonia), otorhinolaryngology infects, urinary system infection, Sepsis, meningitis, preventing post-operation infection, bone and the infection of joint, Skin and soft tissue infection, genital system infection (comprising gonorrhoea), general satisfactory effect, also can be used for wound infection, abdominal infection etc.In 1992 first in Discussion on Chinese Listed.Through the development of twenties years, rely on its has a broad antifungal spectrum, determined curative effect, and the advantage such as the huge market space, ceftriaxone sodium has become leading product very important on microbiotic market.In the sales achievement of recent years, rank among the best always.The medicines such as ceftriaxone sodium are put into " national Basic Medical Insurance for Urban Employees medicine ", use in total amount and occupy very large share at national various big hospital microbiotic, and the status in national health industry is very important.
The synthetic method of triazine ring mainly contains following two kinds at present:
Route 1, molecule inner ring condensation: 1996, Clive L.Branch synthesized TZT by the method for molecule inner ring condensation.Its concrete scheme is taking 2-methylthiosemicarbazone and methyl malonyl chloride synthetic 1-oxamyl thiosemicarbazide under the effect of raw material reagent in tetrahydrofuran (THF), then under alkaline reagents, after self molecule inner ring condensation, obtains triazine ring after ion exchange resin.
The intermolecular cyclization of route 2: be taking 2-methylthiosemicarbazone (or salt of 2-methylthiosemicarbazone) as starting raw material, reaction generates 2-methylthiosemicarbazone with oxalic acid diethyl ester, then under alkaline condition, carry out condensation reaction with oxalic acid diethyl ester, generate triazine ring sodium salt, finally under acidic conditions, refine and obtain final finished product triazine ring.
, there is following shortcoming in the above two lines of comprehensive analysis:
1, synthetic route 1, the route of the technique of molecule inner ring condensation is more complicated, especially the preparation complexity of raw material methyl malonyl chloride, yield lower (80% left and right), and it is highly active acyl chloride intermediate, operation inconvenience, it must make spent ion exchange resin carry out purifying simultaneously, complex process, and cost is very high, be not suitable for suitability for industrialized production, without actual production meaning.
2, synthetic route 2, intermolecular cyclization process is in second step cyclization process, need a large amount of solvent systems just can complete, traditional reaction process is used single solvent system simultaneously, causes very thickness of system, cause partial concn inhomogeneous, under the existence of local excess base, generate by product 1-methyl-5-sulfydryl-1,2,4-triazole-3-carboxylate methyl ester, causes cyclization yield on the low side.This by product is difficult to remove and becomes the important impurity that affects product quality in follow-up sepn process simultaneously.
Summary of the invention
The object of the present invention is to provide a kind of novel method that uses the synthetic triazine ring of mixed solvent, be optimized for the reaction system in cyclization process, reaction is carried out in a uniform environment, make by product (1-methyl-5-sulfydryl-1,2,4-triazole-3-carboxylate methyl ester) content is controlled at below 20ppm, more than triazine ring cyclization yield is brought up to 90% (in 2-methylthiourea).
The technical solution adopted for the present invention to solve the technical problems is: a kind of novel method that uses the synthetic triazine ring of mixed solvent, synthesis technique is: 2-methylthiosemicarbazone, mixed solvent, oxalic acid diethyl ester, sodium methylate carry out ring-closure reaction at 0-45 DEG C and generate triazine ring sodium salt, then obtain triazine ring through hcl acidifying.
Particularly, the mass ratio of described mixed solvent and 2-methylthiosemicarbazone is 10:1-20:1.
Particularly, described mixed solvent is the mixture of a kind of polar aprotic solvent and a kind of polar aprotic solvent, and the mass ratio of described protonic solvent and aprotic solvent is 1:0.75-1:3.5.
Particularly, the one in described protonic solvent is aliphatic C1-C4 alcohols, aliphatic tertiary amine.
Preferably, described protonic solvent is methyl alcohol.
Particularly, described aprotic solvent is the one in DMF, DMSO, NMP, HMPA, acetone, acetonitrile, dioxane, THF.
Preferably, described aprotic solvent is DMSO.
Particularly, the mass ratio of described oxalic acid diethyl ester and 2-methylthiosemicarbazone is 3:1-5:1.
Particularly, the mass ratio of described sodium methylate and 2-methylthiosemicarbazone is 6:1-15:1.
Particularly, the consumption of described hydrochloric acid is the 15-50% of 2-methylthiosemicarbazone consumption.
The present invention has following beneficial effect: by the use of mixed solvent, the system viscosity of building-up process is significantly improved, TTZ cyclization yield has been brought up to more than 90% (in 2-methylthiosemicarbazone), by product 1-methyl-5-sulfydryl-1,2,4-triazole-3-carboxylate methyl ester content is below 0.002%, lower than below 20ppm.
Embodiment
Be below specific embodiments of the invention, technical scheme of the present invention is described further, but protection scope of the present invention is not limited to these embodiment.Every do not deviate from the change of the present invention design or be equal to substitute include within protection scope of the present invention.
Embodiment 1:
1:10:4:10 adds 2-methylthiosemicarbazone in reactor in mass ratio, mixed solvent, oxalic acid diethyl ester, sodium methylate, wherein, mixed solvent is methyl alcohol, the mixture of DMSO, the mass ratio of methyl alcohol and DMSO is 1:3, carry out ring-closure reaction at 0-45 DEG C, reaction is finished, through hcl acidifying, the consumption of hydrochloric acid is 30% of 2-methylthiosemicarbazone consumption, then filter, the dry triazine ring that obtains, yield 91.6%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-products content (HPLC) 0.0005% (5ppm).
Embodiment 2:
1:20:3:6 adds 2-methylthiosemicarbazone in reactor in mass ratio, mixed solvent, oxalic acid diethyl ester, sodium methylate, wherein, mixed solvent is ethanol, the mixture of NMP, the mass ratio of ethanol and NMP is 1:0.75, carry out ring-closure reaction at 0-45 DEG C, reaction is finished, through hcl acidifying, the consumption of hydrochloric acid is 40% of 2-methylthiosemicarbazone consumption, then filter, the dry triazine ring that obtains, yield 90.5%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-products content (HPLC) 0.0008% (8ppm).
Embodiment 3:
1:15:5:15 adds 2-methylthiosemicarbazone in reactor in mass ratio, mixed solvent, oxalic acid diethyl ester, sodium methylate, wherein, mixed solvent is methyl alcohol, the mixture of DMF, the mass ratio of methyl alcohol and DMF is 1:2, carry out ring-closure reaction at 0-45 DEG C, reaction is finished, through hcl acidifying, the consumption of hydrochloric acid is 50% of 2-methylthiosemicarbazone consumption, then filter, the dry triazine ring that obtains, yield 90.8%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-products content (HPLC) 0.0011% (11ppm).
Embodiment 4:
1:20:4:8 adds 2-methylthiosemicarbazone in reactor in mass ratio, mixed solvent, oxalic acid diethyl ester, sodium methylate, wherein, mixed solvent is ethanol, the mixture of acetonitrile, the mass ratio of ethanol and acetonitrile is 1:3.5, carry out ring-closure reaction at 0-45 DEG C, reaction is finished, through hcl acidifying, the consumption of hydrochloric acid is 15% of 2-methylthiosemicarbazone consumption, then filter, the dry triazine ring that obtains, yield 91.1%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-products content (HPLC) 0.0006% (6ppm).
Embodiment 5:
1:10:5:12 adds 2-methylthiosemicarbazone in reactor in mass ratio, mixed solvent, oxalic acid diethyl ester, sodium methylate, wherein, mixed solvent is methyl alcohol, the mixture of acetone, the mass ratio of methyl alcohol and acetone is 1:1.5, carry out ring-closure reaction at 0-45 DEG C, reaction is finished, through hcl acidifying, the consumption of hydrochloric acid is 25% of 2-methylthiosemicarbazone consumption, then filter, the dry triazine ring that obtains, yield 90.6%, { calculation formula=M (triazine ring)/[M (methylthiosemicarbazone) * 159.17/105.16] }, by-products content (HPLC) 0.0014% (14ppm).
Claims (10)
1. one kind uses the novel method of the synthetic triazine ring of mixed solvent, it is characterized in that, synthesis technique is: 2-methylthiosemicarbazone, mixed solvent, oxalic acid diethyl ester, sodium methylate carry out ring-closure reaction at 0-45 DEG C and generate triazine ring sodium salt, then obtain triazine ring through hcl acidifying.
2. the novel method of the synthetic triazine ring of use mixed solvent according to claim 1, is characterized in that, the mass ratio of described mixed solvent and 2-methylthiosemicarbazone is 10:1-20:1.
3. the novel method of the synthetic triazine ring of use mixed solvent according to claim 1 and 2, it is characterized in that, described mixed solvent is the mixture of a kind of polar aprotic solvent and a kind of polar aprotic solvent, and the mass ratio of described protonic solvent and aprotic solvent is 1:0.75-1:3.5.
4. the novel method of the synthetic triazine ring of use mixed solvent according to claim 3, is characterized in that the one in alcohols, aliphatic tertiary amine that described protonic solvent is aliphatic C1-C4.
5. the novel method of the synthetic triazine ring of use mixed solvent according to claim 4, is characterized in that, described protonic solvent is methyl alcohol.
6. the novel method of the synthetic triazine ring of use mixed solvent according to claim 3, is characterized in that, described aprotic solvent is the one in DMF, DMSO, NMP, HMPA, acetone, acetonitrile, dioxane, THF.
7. the novel method of the synthetic triazine ring of use mixed solvent according to claim 6, is characterized in that, described aprotic solvent is DMSO.
8. the novel method of the synthetic triazine ring of use mixed solvent according to claim 1, is characterized in that, the mass ratio of described oxalic acid diethyl ester and 2-methylthiosemicarbazone is 3:1-5:1.
9. the novel method of the synthetic triazine ring of use mixed solvent according to claim 1, is characterized in that, the mass ratio of described sodium methylate and 2-methylthiosemicarbazone is 6:1-15:1.
10. the novel method of the synthetic triazine ring of use mixed solvent according to claim 1, is characterized in that, the consumption of described hydrochloric acid is the 15-50% of 2-methylthiosemicarbazone consumption.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749063A (en) * | 2016-11-14 | 2017-05-31 | 山东汇海医药化工有限公司 | The method that a kind of self-control organic alkali catalyst of use with Graphene as carrier synthesizes triazine ring |
| CN107235837A (en) * | 2017-03-22 | 2017-10-10 | 扬子江药业集团有限公司 | A kind of preparation method of Fenofibric Acid |
| CN109293590A (en) * | 2018-11-23 | 2019-02-01 | 山东汇海医药化工有限公司 | A method of promoting triazine ring product quality |
| CN109336831A (en) * | 2018-11-23 | 2019-02-15 | 山东汇海医药化工有限公司 | A method of recycling triazine ring from triazine ring waste water |
| CN110950814A (en) * | 2019-12-11 | 2020-04-03 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring refining wastewater |
| CN110981823A (en) * | 2019-12-27 | 2020-04-10 | 山东汇海医药化工有限公司 | Method for preparing 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring |
| CN111057017A (en) * | 2019-12-27 | 2020-04-24 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring cyclization mother liquor |
| CN112209892A (en) * | 2020-10-20 | 2021-01-12 | 山东汇海医药化工有限公司 | Preparation method of high-melting-point triazine ring product |
| CN112694448A (en) * | 2020-12-30 | 2021-04-23 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
| CN112759558A (en) * | 2020-12-30 | 2021-05-07 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749063A (en) * | 2016-11-14 | 2017-05-31 | 山东汇海医药化工有限公司 | The method that a kind of self-control organic alkali catalyst of use with Graphene as carrier synthesizes triazine ring |
| CN107235837A (en) * | 2017-03-22 | 2017-10-10 | 扬子江药业集团有限公司 | A kind of preparation method of Fenofibric Acid |
| CN107235837B (en) * | 2017-03-22 | 2020-08-04 | 扬子江药业集团有限公司 | Preparation method of fenofibric acid |
| CN109293590A (en) * | 2018-11-23 | 2019-02-01 | 山东汇海医药化工有限公司 | A method of promoting triazine ring product quality |
| CN109336831A (en) * | 2018-11-23 | 2019-02-15 | 山东汇海医药化工有限公司 | A method of recycling triazine ring from triazine ring waste water |
| CN110950814A (en) * | 2019-12-11 | 2020-04-03 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring refining wastewater |
| CN111057017A (en) * | 2019-12-27 | 2020-04-24 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring cyclization mother liquor |
| CN110981823A (en) * | 2019-12-27 | 2020-04-10 | 山东汇海医药化工有限公司 | Method for preparing 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring |
| CN111057017B (en) * | 2019-12-27 | 2021-07-30 | 山东汇海医药化工有限公司 | Method for recovering 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring cyclization mother liquor |
| CN110981823B (en) * | 2019-12-27 | 2021-08-03 | 山东汇海医药化工有限公司 | Method for preparing 3-mercapto-5-methyl-1, 2, 4-triazole from triazine ring |
| CN112209892A (en) * | 2020-10-20 | 2021-01-12 | 山东汇海医药化工有限公司 | Preparation method of high-melting-point triazine ring product |
| CN112694448A (en) * | 2020-12-30 | 2021-04-23 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
| CN112759558A (en) * | 2020-12-30 | 2021-05-07 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
| CN112759558B (en) * | 2020-12-30 | 2022-06-14 | 山东金城柯瑞化学有限公司 | Process for the preparation of triazine rings |
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Denomination of invention: A new method for synthesis of triazine ring using mixed solvent Effective date of registration: 20211130 Granted publication date: 20170915 Pledgee: Dongying Hekou District sub branch of China Post Savings Bank Co.,Ltd. Pledgor: SHANDONG HUIHAI PHARMACEUTICAL& CHEMICAL Co.,Ltd. Registration number: Y2021980013568 |
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